EP1513847A2 - Crystallization and purification of macrolides - Google Patents
Crystallization and purification of macrolidesInfo
- Publication number
- EP1513847A2 EP1513847A2 EP04758730A EP04758730A EP1513847A2 EP 1513847 A2 EP1513847 A2 EP 1513847A2 EP 04758730 A EP04758730 A EP 04758730A EP 04758730 A EP04758730 A EP 04758730A EP 1513847 A2 EP1513847 A2 EP 1513847A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- macrolide
- water
- rich phase
- combination
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000003120 macrolide antibiotic agent Substances 0.000 title claims abstract description 92
- 238000002425 crystallisation Methods 0.000 title abstract description 30
- 230000008025 crystallization Effects 0.000 title abstract description 30
- 238000000746 purification Methods 0.000 title abstract description 8
- 229940041033 macrolides Drugs 0.000 title description 13
- 238000000034 method Methods 0.000 claims abstract description 51
- 239000002904 solvent Substances 0.000 claims abstract description 40
- 239000002798 polar solvent Substances 0.000 claims abstract description 28
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 24
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 24
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 23
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims abstract description 20
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims abstract description 19
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims abstract description 19
- 229960002930 sirolimus Drugs 0.000 claims abstract description 19
- 229960001967 tacrolimus Drugs 0.000 claims abstract description 19
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims abstract description 19
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims abstract description 17
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 claims abstract description 16
- 229960005167 everolimus Drugs 0.000 claims abstract description 15
- 229960005330 pimecrolimus Drugs 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 56
- -1 z'so-butanol Chemical compound 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000007858 starting material Substances 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 17
- 238000000605 extraction Methods 0.000 claims description 16
- 239000012141 concentrate Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 4
- 239000000920 calcium hydroxide Substances 0.000 claims description 4
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 4
- 229940113088 dimethylacetamide Drugs 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 11
- 229910000069 nitrogen hydride Inorganic materials 0.000 claims 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 2
- 150000002825 nitriles Chemical class 0.000 claims 2
- 239000000010 aprotic solvent Substances 0.000 abstract description 7
- 239000000243 solution Substances 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 8
- 238000000855 fermentation Methods 0.000 description 7
- 230000004151 fermentation Effects 0.000 description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
- 125000002015 acyclic group Chemical group 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 150000007529 inorganic bases Chemical class 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 4
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 4
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000005907 alkyl ester group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- ZDQSOHOQTUFQEM-PKUCKEGBSA-N ascomycin Chemical class C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C\C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-PKUCKEGBSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- ZDQSOHOQTUFQEM-XCXYXIJFSA-N ascomycin Natural products CC[C@H]1C=C(C)C[C@@H](C)C[C@@H](OC)[C@H]2O[C@@](O)([C@@H](C)C[C@H]2OC)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O[C@H]([C@H](C)[C@@H](O)CC1=O)C(=C[C@@H]4CC[C@@H](O)[C@H](C4)OC)C ZDQSOHOQTUFQEM-XCXYXIJFSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229940086542 triethylamine Drugs 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AVMSWPWPYJVYKY-UHFFFAOYSA-N 2-Methylpropyl formate Chemical compound CC(C)COC=O AVMSWPWPYJVYKY-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KFNNIILCVOLYIR-UHFFFAOYSA-N Propyl formate Chemical compound CCCOC=O KFNNIILCVOLYIR-UHFFFAOYSA-N 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241000187398 Streptomyces lividans Species 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000008266 deoxy sugars Chemical class 0.000 description 1
- 150000002012 dioxanes Chemical class 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 125000000686 lactone group Chemical group 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
Definitions
- the present invention relates to the crystallization and purification of macrolides, especially tacrolimus, sirolimus (rapamycin), pimecrolimus, and everolimus.
- the present invention relates to a method for crystallization and purification of macrolides, especially tacrolimus, sirolimus, pimecrolimus, and everolimus, including the steps of: providing a combination of a macrolide starting material; a polar solvent, especially a polar solvent that is an alkyl ester of an alkanoic acid, an alcohol, an ether, an aliphatic ketone, an aliphatic nitrile, or a dipolar aprotic solvent; a hydrocarbon solvent, especially an acyclic or cyclic aliphatic hydrocarbon or an aromatic hydrocarbon (e.g.
- toluene toluene
- water at a pH of about 7 or above, especially about 8 or above; maintaining the combination at a temperature of between about -15°C to about 50°C, preferably between about -5°C to about 40°C, most preferably between about -2°C to about 35°C for at least about 1 hour, preferably between about 48 to about 100 hours; and isolating crystalline macrolide.
- the present invention relates to a method for crystallization and purification of a macrolide, especially tacrolimus, sirolimus, pimecrolimus, or everolimus including the steps of: providing a concentrate residue from whole-broth extraction of macrolide-containing biomatter in a polar solvent, especially a polar solvent that is an alkyl ester of an alkanoic acid, an alcohol, an ether, an aliphatic ketone, an aliphatic nitrile, or a dipolar aprotic solvent; combining the solution, in any order, with water and a hydrocarbon solvent, especially an acyclic or cyclic aliphatic hydrocarbon or an aromatic hydrocarbon (e.g.
- the present invention relates to a method of crystallizing and purifying a macrolide, especially tacrolimus, sirolimus, pimecrolimus, or everolimus including the steps of: combining, in any order, an oil that is a concentrate obtained by concentrating a solution obtained by extracting macrolide-containing biomatter with a hydrophobic extraction solvent, e.g.
- a polar solvent especially a polar solvent that is an alkyl ester of an alkanoic acid, an alcohol, an ether, an aliphatic ketone, an aliphatic nitrile, or a dipolar aprotic solvent
- a hydrocarbon solvent especially an acyclic or cyclic aliphatic hydrocarbon or an aromatic hydrocarbon (e.g. toluene); and water; wherein the pH is about 7 or above, especially 8 or above; maintaining the combination at a first crystallization temperature for a first crystallization time; and isolating crystalline macrolide.
- the combination can be, but need not be, maintained at a second crystallization temperature for a second crystallization time.
- ambient temperature refers to a temperature of about 18°C to about 25° C.
- R refers to the registry number assigned to a chemical compound by the Chemical Abstracts Service, Columbus OH, USA).
- the method of the present invention is applied to the crystallization and purification of macrolides from macrolide-containing starting material.
- the macrolides are multi-membered lactone rings having one or more deoxy sugars as substituents.
- Erythromycin, azithromycin, and clarithromycin are macrolides that have bacteriostatic and / or bactericidal activity.
- the macrolides tacrolimus (FK 506) and sirolimus (rapamycin) are preferred macrolides for use in the practice of the present invention.
- the macrolides are typically obtained by fermentation, although synthetic routes to some are known.
- the macrolide starting material for use in the practice of the present invention can be from any source. Concentrate residue from concentrating the extract of the entire fermentation broth ("whole broth method") from macrolide-containing biomatter can be used as the macrolide starting material for the present method.
- Oily residue from macrolide-producing procedsses can also be used as starting macrolide starting material.
- Preferred macrolide-containing biomatter that can be a source of macrolide starting material for the practice of the present invention includes tacrolimus-containing biomatter, particularly fermentation broth obtainable by fermentation using a tacrolimus- producing microorganism, for example, Streptomyces tsuk baensis, new and mutated strains thereof, Streptomyces hygroscopicus, and Streptomyces lividans, as described in United States Patent numbers 4,894,366, 5,116,756, 5,624,842, 5,496,727, and 5,622,866, all of which are incorporated herein by reference.
- Sirolimus-containing (rapamycin- containing) biomatter is also a preferred macrolide-containing biomatter.
- Sirolimus can be produced by fermentation of Streptomyces hygroscopicus, NRRL 5491, as described in United States Patent 3,993,749, incorporated herein by reference.
- Pimecrolimus-containing biomatter and everolimus-containing biomatter are also examples of preferred macrolide-containing biomatter for use in the practice of the method of the present invention.
- Ascomycin-conyaining biomatter is also a preferred macrolide-containing biomatter for use in the practice of the present invention
- Polar solvents are organic compounds, normally liquid at ambient temperature, that dissolve a macrolide, especially tacrolimus, sirolimus, pimecrolimus, or everolimus.
- Polar solvents useful in the practice of the present invention include esters, alcohols, aliphatic nitriles, acyclic and cyclic aliphatic ethers, aliphatic ketones, and dipolar aprotic solvents.
- Esters useful in the practice of the present invention have the general formula Ri-
- esters include methyl acetate, ethyl acetate, n-propyl acetate, iso- propyl acetate, n-butyl acetate, tso-butyl acetate, methyl formate, n-propyl formate, iso- propyl formate, H-butyl formate, and iso-butyl formate, to mention just a few.
- Alcohols useful in the practice of the present invention include methanol, ethanol, H-propanol, wo-propanol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, amyl alcohol and benzyl alcohol, to mention just a few.
- Aliphatic ketones useful in the practice of the present invention have the general formula R ⁇ -C(O)-R 2 , wherein Ri and R 2 are, independently, linear or branched alkyl groups, each having from 1 to 4 carbon atoms.
- Examples of aliphatic ketones include acetone, methyl ethyl ketone, and methyl tso-butyl ketone, to mention just three.
- aliphatic nitriles useful in the practice of the present invention include acetonitrile, propionitrile, and butyronitrile, to mention just three.
- Ethers useful in the practice of the present invention include both acyclic and cyclic aliphatic ethers.
- Acyclic aliphatic ethers have the general formula R ⁇ -O-R 2 , wherein Ri and R 2 are as defined above.
- Examples of acyclic aliphatic ethers include diethyl ether, di- «-propyl ether, and ethyl «-propyl ether, to mention just a few.
- Tetrahydrofuran and the dioxanes are examples of cyclic aliphatic ethers useful in the practice of the present invention.
- Dipolar aprotic solvents are well known to the skilled artisan.
- Dimethyl acetamide (DMAC), dimethyl formamide (DMF), N-methyl-2-pyrrolidone (NMP), acatamide, dioxane and dioxalane are examples of dipolar aprotic solvents useful in the practice of the present invention.
- Hydrocarbon solvents are organic compounds, normally liquid at ambient temperature, that are poor solvents for macrolides.
- the hydrocarbon solvents can be aliphatic hydrocarbon solvents, or they can be aromatic hydrocarbon solvents.
- the aliphatic hydrocarbon solvents can be acj ⁇ clic or they can be cyclic.
- Acyclic hydrocarbon solvents can be linear or branched and have the general formula C n H 2n+2 , where n is from about 5 to about 10.
- 7z-Hexane, n-heptane, octane and zso-octane are examples of preferred acyclic aliphatic hydrocarbon solvents.
- Cyclohexane and methylcyclohexane are examples of cyclic aliphatic hydrocarbon solvents.
- aromatic hydrocarbon solvents include benzene, toluene, the xylenes, and the tetralins, to mention just a few.
- any base organic or inorganic, can be used in the practice of the present invention.
- inorganic bases include ammonia, alkali and alkaline earth metal hydroxides, bicarbonates, and carbonates, to mention just a few.
- the amines are examples of organic bases that can be used in the practice of the present invention.
- the present invention provides a method for crystallization and purification of a macrolide, preferably tacrolimus, sirolimus, pimecrolimus, or everolimus including the steps of: providing, in a crystallization vessel, a combination of a macrohde starting material, a polar solvent, a hydrocarbon solvent, and water, whereby a water rich phase is formed.
- a water-rich phase is a phase in with the majority of the solvent is water and can contain other solvents and solutes.
- the pH of the water-rich phase is or is adjusted to be about 7 or above, preferably about 8 or above. The pH can be adjusted by addition of base.
- the combination is provided, preferably with agitation, and is maintained at a temperature of between about -15°C to about 50°C, preferably between about -5°C to about 40°C, most preferably between about -2°C to about 35°C for at least about 1 hour, preferably between about 48 to about 100 hours, whereby a macrolide-rich phase forms.
- the manner in which the provided combination is assembled is irrelevant to the practice of the present invention.
- the components of the combination can be assembled in any order, or they can be assembled simultaneously.
- crystallization vessel crystallization space
- agitator a crystallization vessel provided with an agitator.
- the design and peculiar characteristics of the crystallization vessel are unimportant and the skilled artisan will know to select the crystallization vessel and agitator based on, among other things, the volume of the combination and the process variables.
- the combination provided will include two or more phases, at least one of which is water-rich.
- the pH of the water-rich phase is about 7 or above, preferably about 8 or above.
- the pH of the water-rich phase can be constant throughout the total crystallization time, or it can be varied in the course of the crystallization time, provided the pH is always at least about 7 or above.
- the desired pH is established with the use of any available inorganic or organic base and the desired pH can be established in any manner or sequence.
- the pH of the water used to assemble the combination can be adjusted, prior to assembly of the combination, with an inorganic or organic base.
- water will be understood to include dilute aqueous solutions (water solutions) of inorganic or organic bases, e.g., N/10 NaOH aq , N/10 OH, N/10 Ca(OH) 2 , N/10 NH 3aq , N/10 (C 2 H 5 ) 3 N aq , N/10 diethylamine or triethyl amine, N/10 pyridine etc.
- Base can be added before the water-rich phase is established by, for example, admitting a low-boiling amine, e.g. methylamine, before water is introduced.
- a low-boiling amine e.g. methylamine
- the pH can be adjusted after the combination is assembled by adding inorganic base, neat, especially as a gas, or in solution in a suitable solvent, e.g. water.
- the pH can be adjusted in increments.
- the pH of the water used to assemble the combination can be adjusted to, e.g., ca. 7 before the combination is assembled and, after assembly, the pH of the water-rich phase can be further adjusted, e.g. to pH 8, by the addition of base, neat or in solution.
- crystalline macrolide is isolated by any of the common methods, for example filtration (gravity or pressure-assisted) or centrifugation, to mention just two. The purity of the isolated crystalline macrolide rivals that of macrolide purified by multiple-pass chromatography.
- the combination provided is assembled by the steps of providing macrolide starting material that is a solution of macrolide, or a concentrate from macrolide extraction, preferably tacrolimus, sirolimus, pimecrolimus, or everolimus in a polar solvent and combining the solution, in any order, with hydrocarbon solvent and water.
- macrolide starting material that is a solution of macrolide, or a concentrate from macrolide extraction, preferably tacrolimus, sirolimus, pimecrolimus, or everolimus in a polar solvent
- the solution provided can be made by any means or method.
- the concentration of the solution provided is not critical and will generally be between about 0.05 g/mL (g macrolide per mL polar solvent) and about 0.3 g/mL.
- the macrolide can come from any source and can be a solid, semi-solid, or an oil (especially an oil that is a residue from concentration of extract from a whole-broth extraction of macrolide-containing biomatter).
- the relative volumes of solution, water, and hydrocarbon solvent are not critical. Typically, the ratio of the volume of solution to the volume of hydrocarbon solvent will be between about 1 :2 and about 1:10. The ratio of the volume of solution to the volume of water will typically be between about 1 :8 to about 1 :25.
- the pH of the water-rich phase can be adjusted and the combination treated as described above.
- the combination provided is assembled by combining, in any order, macrolide starting material, preferably tacrolimus, sirolimus, pimecrolimus, or everolimus starting material, hydrocarbon solvent, polar solvent, and water, wherein the tacrolimus starting material is an oily phase that is a concentrate obtained by concentrating a solution obtained by extracting macrolide-containing biomatter with a hydrophobic extraction solvent, especially wherein the hydrophobic extraction solvent is selected from the group consisting of C2-C6 linear and branched esters of acetic acid or formic acid, C3-C6 linear or branched aliphatic ketones, halogenated methanes, and aromatic hydrocarbons that are liquid at 25° C and that have a boiling point at atmospheric pressure less than about 150°C, wherein the extraction is at a temperature between about 2° C to about 70° C, especially between about 30°C and about 70°C, and at a H of between about 5.5 and about 13, especially between about 7.5 and about 13, to obtain the group consisting
- the oil (macrolide starting material) can first be combined with polar solvent or hydrocarbon solvent or water.
- the order is irrelevant to the practice of the present invention.
- the base required to establish the desired pH can be introduced at any point, or at several points prior to or during the crystallization time.
- the base can be introduced neat, or as a solution, e.g. a solution in water.
- This concentrate was diluted with 167.5 L methanol and 18.6 L water.
- the water - methanol solution was washed with 139.6 L n-Hexane.
- the water-methanol phase was concentrated under reduced pressure to volume of 44 L, and the concentrate was diluted with 44 L water.
- the obtained mixture was extracted with 88 L ethyl acetate.
- the ethyl acetate extract was concentrated to volume of 22.4 L.
- This concentrate of ethyl acetate extract was combined with 158.4L 0.1 M aqueous triethyl amine solution and with 67.3 L n-Hexane. The mixture was stirred at 20° - 25 °C for 3 hours. The mixture was let to stand at 0° - 25 °C for 48 hours (1 minute stirring every hour).
- the crystals formed were isolated by filtration and were suspended first in 83 L 0,1 M aqueous trielhyl amine solution and, second, in 83 L n-Hexane. The crystals were isolated by filtration.
- the crystals were dried at 40 °C under reduced pressure.
- the dried crude tacrolimus had an assay 83 %.
- Crude product contains 1.9 kg tacrolimus.
- the yield of the crystallization step was 91 % .
- Example 2 In the following example, a macrolide (tacrolimus), as an oily concentrate from whole-broth extraction of macrolide-containing biomatter, was combined with polar solvent, hydrocarbon solvent, and water containing a base. The combination was held at a crystallization temperature for a total crystallization time. At the end of the total crystallization time, the crystalline macrolide was isolated. The proportions of components, the process variables, and the results are collected in Table I.
- Fermentation broth containing ascomycin was processed according to example 1. The process resulted in 60 % yield for crude ascomycin.
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Abstract
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US512887P | 2003-10-20 | ||
PCT/US2004/010033 WO2004089958A2 (en) | 2003-03-31 | 2004-03-31 | Crystallization and purification of macrolides |
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KR100859670B1 (en) | 2006-09-13 | 2008-09-23 | 동국제약 주식회사 | A method for purification of tacrolimus with high yield and high purity |
TW200837067A (en) * | 2006-11-06 | 2008-09-16 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Ascomycin and pimecrolimus having reduced levels of desmethylascomycin and 32-deoxy-32-epichloro-desmethylascomycin respectively, and methods for preparation thereof |
AU2006350684B2 (en) * | 2006-11-10 | 2012-07-05 | Biocon Limited | A pure form of rapamycin and a process for recovery and purification thereof |
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US9192697B2 (en) | 2007-07-03 | 2015-11-24 | Hemoteq Ag | Balloon catheter for treating stenosis of body passages and for preventing threatening restenosis |
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WO2011005421A2 (en) | 2009-07-10 | 2011-01-13 | Boston Scientific Scimed, Inc. | Use of nanocrystals for a drug delivery balloon |
EP2453938B1 (en) | 2009-07-17 | 2015-08-19 | Boston Scientific Scimed, Inc. | Nucleation of drug delivery balloons to provide improved crystal size and density |
WO2011081712A1 (en) * | 2009-12-31 | 2011-07-07 | Boston Scientific Scimed, Inc. | Cryo activated drug delivery and cutting balloons |
WO2012031236A1 (en) | 2010-09-02 | 2012-03-08 | Boston Scientific Scimed, Inc. | Coating process for drug delivery balloons using heat-induced rewrap memory |
WO2013022458A1 (en) * | 2011-08-05 | 2013-02-14 | Boston Scientific Scimed, Inc. | Methods of converting amorphous drug substance into crystalline form |
US9056152B2 (en) | 2011-08-25 | 2015-06-16 | Boston Scientific Scimed, Inc. | Medical device with crystalline drug coating |
CN103159812B (en) * | 2011-12-08 | 2016-03-23 | 湖南中创化工股份有限公司 | A kind of method extracting erythromycin from the erythromycin aqueous solution |
WO2014072984A1 (en) | 2012-11-06 | 2014-05-15 | Natco Pharma Limited | Improved process for isolation and purification of rapamycin from fermentation broth |
CN102942607A (en) * | 2012-11-28 | 2013-02-27 | 宁夏启元药业有限公司 | Method for crystallizing erythrocin by composite solvent |
SG11201507406YA (en) * | 2013-03-15 | 2015-10-29 | Biosensors Int Group Ltd | Purification of rapamycin derivatives |
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JP6416242B2 (en) * | 2013-06-12 | 2018-10-31 | サーモディクス,インコーポレイティド | Solvent method for preparing crystalline macrolide microparticles, composition, and article comprising microparticles |
US10098846B2 (en) | 2016-03-31 | 2018-10-16 | Surmodics, Inc. | Drug-containing particulate composition with cationic agent, associated medical devices, and methods for treatment |
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JP2023519875A (en) * | 2020-03-27 | 2023-05-15 | ボストン サイエンティフィック サイムド,インコーポレイテッド | Method for crystallization of drugs |
US11795146B2 (en) * | 2021-10-11 | 2023-10-24 | Anebulo Pharmaceuticals, Inc. | Crystalline forms of a cannabinoid receptor type 1 (CB1) modulator and methods of use and preparation thereof |
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